Damage to axonal connections is responsible for symptoms in a broad range of neurological conditions. The paralysis and sensory dysfunction of spinal cord trauma epitomize the lack of spontaneous recovery from such deficits. Poor recovery is observed despite the strong intrinsic capacity for growth in response to axotomy. The re-extension of injured axons is restricted by inhibitory molecules in the extracellular milieu of the injured CNS, including Nogo and Chondroitin Sulfate Proteoglycans (CSPGs). Blockade of these inhibitors releases a degree of axonal growth and improves functional outcomes from neurological injury in preclinical studies. We hypothesize that modification of additional molecules and combinations of molecules will accomplish greater adult CNS axonal growth and greater functional recovery. Members of the ephrin, RGM and Sema protein families are candidate adult CNS axonal growth inhibitors. We will utilize specific genetic tools to assess their role in vivo in limiting axonal growth and recovery from spinal cord injury. It is crucial to examine the interactions between these proteins in vivo to determine whether they function redundantly, additively or synergistically. By examining mice lacking functional genes for these selected inhibitors, we will reveal whether specific combinations are particularly advantageous for disinhibiting adult CNS axonal growth and improving neurological recovery. Together these studies will define opportunities for enhancing axonal growth in the injured adult brain and spinal cord. This work is critical to optimize the opportunity for development of clinical methods to increase axonal growth and improve functional recovery from neurological damage.